Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat

Germain, D. P.; Hughes, D. A.; Nicholls, K.; Bichet, D. G.; Giugliani, R.; Wilcox, W. R.; Feliciani, C.; Shankar, S. P.; Ezgu, F.; Amartino, H.; Bratkovic, D.; Feldt-Rasmussen, U.; Nedd, K.; Sharaf El Din, U.; Lourenco, C. M.; Banikazemi, M.; Charrow, J.; Dasouki, M.; Finegold, D.; Giraldo, P.; Goker-Alpan, O.; Longo, N.; Scott, C. R.; Torra, R.; Tuffaha, A.; Jovanovic, A.; Waldek, S.; Packman, S.; Ludington, E.; Viereck, C.; Kirk, J.; Yu, J.; Benjamin, E. R.; Johnson, F.; Lockhart, D. J.; Skuban, N.; Castelli, J.; Barth, J.; Barlow, C.; Schiffmann, R.

N Engl J Med. 2016 Aug 11; 375(6):545-55


BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal alpha-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of alpha-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant alpha-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant alpha-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (>/=50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant alpha-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant alpha-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30+/-0.66 and -1.51+/-1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant alpha-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

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